Gadolinium presence, MRI hyperintensities, and glucose uptake in the hypoperfused rat brain after repeated administrations of gadodiamide

Arena, Francesca; Bardini, Paola; Blasi, Francesco; Gianolio, Eliana; Marini, Giada M.; Cava, Francesca La; Valbusa, Giovanni; Aime, Silvio

doi:10.1007/s00234-018-2120-3

Cited by 14 publications

(12 citation statements)

References 39 publications

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“…A previous study has shown that increased white matter degeneration due to hypoperfusion in rats with CCH using the BCCAO approach was also accompanied by an increased loss of oligodendrocytes and neuroinflammation (Choi et al, 2016). Moreover, a recent study supports the fact that a larger number of WMHs (from gadolinium-contrast MRI) found in subcortical brain regions of BCCAO rats is suggestive of the BBB’s perturbed permeability (Arena et al, 2019). Another example of a hypoperfused model is low-density lipoprotein receptor knockout mice to demonstrate the relationship between hypercholesterolemia and CSVD (Hainsworth and Markus, 2008; Tiwari et al, 2018).…”

Section: Experimental Animal Model For Csvdmentioning

confidence: 60%

Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

et al. 2019

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Cerebral small vessel disease (CSVD) refers to a spectrum of clinical and imaging findings resulting from pathological processes of various etiologies affecting cerebral arterioles, perforating arteries, capillaries, and venules. Unlike large vessels, it is a challenge to visualize small vessels in vivo, hence the difficulty to directly monitor the natural progression of the disease. CSVD might progress for many years during the early stage of the disease as it remains asymptomatic. Prevalent among elderly individuals, CSVD has been alarmingly reported as an important precursor of full-blown stroke and vascular dementia. Growing evidence has also shown a significant association between CSVD’s radiological manifestation with dementia and Alzheimer’s disease (AD) pathology. Although it remains contentious as to whether CSVD is a cause or sequelae of AD, it is not far-fetched to posit that effective therapeutic measures of CSVD would mitigate the overall burden of dementia. Nevertheless, the unifying theory on the pathomechanism of the disease remains elusive, hence the lack of effective therapeutic approaches. Thus, this chapter consolidates the contemporary insights from numerous experimental animal models of CSVD, to date: from the available experimental animal models of CSVD and its translational research value; the pathomechanical aspects of the disease; relevant aspects on systems biology; opportunities for early disease biomarkers; and finally, converging approaches for future therapeutic directions of CSVD.

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Section: Experimental Animal Model For Csvdmentioning

confidence: 60%

Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

et al. 2019

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“…The used dose per injection of 1.8 mmol/kg corresponds to a human dose of 0.3 mmol/kg. The cumulative dose of 9 mmol/kg is considerably higher than in humans but lower than in the discussed animal studies using a total dose of 13.2 mmol/kg [28] and 20 mmol/kg [29]. In our study, MRI and dissection were done at a single time-point 1 week after the last GBCA administration.…”

Section: Discussionmentioning

confidence: 92%

“…Our results are partly in contrast to other preclinical data. In a chronic hypoperfusion brain model in rats that is associated with BBB alterations, repeated administration of linear gadodiamide (cumulative dose 13.2 mmol/kg) led to higher T1-weighted SIs in the DCN and higher Gd concentrations in the cerebellum and subcortical region [28]. Although the Gd concentrations in the hypoperfused animals were significantly higher compared with the control animals, they differ not substantially (on average 1.2-fold and 1.3-fold for cerebellum and subcortical region, respectively).…”

Section: Discussionmentioning

confidence: 99%

Impact of brain tumors and radiotherapy on the presence of gadolinium in the brain after repeated administration of gadolinium-based contrast agents: an experimental study in rats

et al. 2019

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PurposeTo investigate the impact of blood-brain barrier (BBB) alterations induced by an experimental tumor and radiotherapy on MRI signal intensity (SI) in deep cerebellar nuclei (DCN) and the presence of gadolinium after repeated administration of a linear gadolinium-based contrast agent in rats.MethodsEighteen Fischer rats were divided into a tumor (gliosarcoma, GS9L model), a radiotherapy, and a control group. All animals received 5 daily injections (1.8 mmol/kg) of gadopentetate dimeglumine. For tumor-bearing animals, the BBB disruption was confirmed by contrast-enhanced MRI. Animals from the tumor and radiation group underwent radiotherapy in 6 fractions of 5 Gray. The SI ratio between DCN and brain stem was evaluated on T1-weigthed MRI at baseline and 1 week after the last administration. Subsequently, the brain was dissected for gadolinium quantification by inductively coupled plasma-mass spectrometry. Statistical analysis was done with the Kruskal-Wallis test.ResultsAn increased but similar DCN/brain stem SI ratio was found for all three groups (p = 0.14). The gadolinium tissue concentrations (median, nmol/g) were 6.7 (tumor), 6.3 (radiotherapy), and 6.8 (control) in the cerebellum (p = 0.64) and 17.8/14.6 (tumor), 20.0/18.9 (radiotherapy), and 17.8/15.9 (control) for the primary tumor (p = 0.98) and the contralateral hemisphere (p = 0.41) of the cerebrum, respectively.ConclusionAn experimental brain tumor treated by radiotherapy or radiotherapy alone did not alter DCN signal hyperintensity and gadolinium concentration in the rat brain 1 week after repeated administration of gadopentetate. This suggests that a local BBB disruption does not affect the amount of retained gadolinium in the brain.

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“…In accordance with literature, 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET) imaging of rats who had received a cumulative dose of gadodiamide (13.2 mmol/kg over 7 weeks) did not reveal any abnormal glucose uptake in the DCN, and thus even with chronic cerebral hypoperfusion (model of aging and neurodegenerative diseases). 31 However, a 18 F-FDG-PET study had shown a lower maximum standardized uptake value (SUVmax) in DCN of patients who had received repeated injections of GBCAs (3 to 6 injections without distinction between macrocyclic and linear forms) compared to those who had not received, which might indicate a decrease of glucose metabolism. 32 Nevertheless, it should be taken under consideration that 1 H MRS may not be sensitive enough to detect any subtle modifications of cerebellar metabolism.…”

Section: Discussionmentioning

confidence: 99%

Effect of Long-Term Retention of Gadolinium on Metabolism of Deep Cerebellar Nuclei After Repeated Injections of Gadodiamide in Rats

Hamrani¹,

Vivès²,

Buchholz

et al. 2019

Invest Radiol

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Objectives: To determine potential metabolism and histological modifications due to gadolinium retention within deep cerebellar nuclei (DCN) after linear gadolinium based contrast agent injection (gadodiamide) in rats at 1 year after the last injection. Materials and Methods: Twenty rats received 20 doses of gadodiamide (0.6 mmol of gadolinium per kilogram each) over 5 weeks. They were followed at 1 week (M0), 6 weeks (M1) and 54-55 weeks (M13) post-injections to evaluate hypersignal on unenhanced T1weighted MRI and metabolic alterations by 1 H MRS. At 1 year post-injections, brains were sampled to determine the localization of gadolinium within cerebellum by laser ablation inductively coupled mass spectroscopy (LA-ICP-MS) and to evaluate morphological changes by semi-quantitative immunofluorescence analysis. Results: There is a significant increase of the ratio DCN/brainstem for the gadodiamide group at M0 (+7.2% vs control group=0.989±0.01), M1 (+7.6% vs control group=1.002±0.018) and it lasted up to M13 (+4.7% vs control group=0.9862±0.008). No variation among metabolic markers (cellular homeostasis, excitatory neurotransmitter and metabolites specific to a cellular compartment) were detected by 1 H MRS between gadodiamide and saline groups at M0, M1 and M13. At M13, LA-ICP-MS demonstrated that long-term gadolinium retention occurred preferentially in DCN. No histological abnormalities (including analysis of astrocytes, neurons and microglial cells) were found in the rostral part of DCN. Conclusion: Repeated administration of gadodiamide lead to a retention of gadolinium preferentially within DCN until 1-year post-injections. This retention did not lead to any detectable changes of metabolic biomarkers nor histological alterations.

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Gadolinium presence, MRI hyperintensities, and glucose uptake in the hypoperfused rat brain after repeated administrations of gadodiamide

Cited by 14 publications

References 39 publications

Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

Cerebral Small Vessel Disease (CSVD) – Lessons From the Animal Models

Impact of brain tumors and radiotherapy on the presence of gadolinium in the brain after repeated administration of gadolinium-based contrast agents: an experimental study in rats

Effect of Long-Term Retention of Gadolinium on Metabolism of Deep Cerebellar Nuclei After Repeated Injections of Gadodiamide in Rats

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